Diet drug makers seeking new strategies

Regulators set a high bar for new obesity medicines

Becky Patterson, 53, of Oceanside, participated in a 13-month clinical trial of Contrave, a therapy made by La Jolla-based Orexigen Therapeutics. It was one of the three new drugs rejected recently by regulators.
— Charlie Neuman

Becky Patterson, 53, of Oceanside, participated in a 13-month clinical trial of Contrave, a therapy made by La Jolla-based Orexigen Therapeutics. It was one of the three new drugs rejected recently by regulators.
— Charlie Neuman

After spending more than $1 billion developing new prescription diet pills to curb the nation’s fast-growing obesity epidemic, the pharmaceutical industry has struck out.

Three times in recent months, regulators have rejected new drugs because of concerns over potentially harmful side effects. The failures have left drugmakers, including some in San Diego County, wondering what they have to do.

Overcoming the Food and Drug Administration’s fear of unleashing an unsafe diet pill among millions of Americans will require testing a drug on more people for a longer amount of time, developing a new regulatory strategy or pursuing an entirely different biological approach to the health problem, drug industry experts say.

One option is taking a less ambitious regulatory review route that would limit the drug to a far smaller and higher-risk group of patients, at least initially. Or the pill could be launched overseas, where a wider body of evidence could be gathered before seeking U.S. approval.

Another alternative is forgoing work on drugs that act on the psychological elements of overeating, which carry with them certain risks associated with brain function. All three of the diet pills that were recently rejected by the FDA take this approach.

Instead, drugmakers could focus on drugs targeting different biological pathways, such as metabolic therapies that alter the way the body stores and consumes energy.

“The problem really is an interesting paradox,” said John “Chip” Scarlett, a physician, scientist and chief executive of Vega Therapeutics, a Bay Area startup targeting inflammation as a way to treat diabetes.

As the need for new weight-loss drugs increases, he said, so does the risk faced by regulators for approving therapies that have been tested in only a few thousand people.

“The FDA has been really clear,” said Jim DiBiasi, a Long Beach-based partner with 3D Communications who has helped prepare drug company executives for FDA reviews, including some involving weight-loss therapies.

“It’s all about safety,” he said. “When companies come to the market with one year of (clinical trial data), the FDA says that’s not enough.”

Few people question the need for a new medical options.

Doctors recommend a proper diet and exercise, but most people who try those conventional methods either fail or end up regaining the weight they lost. Only one prescription diet pill, Xenical, is currently available in the United States for long-term use.

The mandate for attacking the problem has never been stronger.

With more than two-thirds of U.S. adults considered overweight or obese, annual costs associated with the conditions have reached $270 billion, according to a new report from the Society of Actuaries.

Meanwhile, a fast-growing body of research has tied obesity to the nation’s biggest health problems — chronic conditions such as diabetes and high blood pressure, heart disease and some cancers.

“Our clinic is overburdened with patients,” said Dr. Ken Fujioka, director of nutrition and metabolic research at Scripps Health in San Diego County. “The problem is getting worse, and we have fewer treatments available.”

Any new diet pill that can survive FDA scrutiny will almost certainly become a blockbuster, generating billions of dollars in sales and big profits for the drugmaker.

But in a nod to the bleak odds that have faced the drug category in recent years, the nation’s biggest pharmaceutical companies have largely avoided investments in the space.

Like millions of other Americans who struggle with their weight every day, Becky Patterson, 53, of Oceanside, said she would take a new diet pill if the FDA said it was safe and effective.

The management recruiter for Sears participated in a 13-month clinical trial of Contrave, a therapy made by La Jolla-based Orexigen Therapeutics that was one of the three new drugs rejected by regulators.

“I was very happy,” she said. “It really did curb my appetite. I stopped eating when I had enough, which was huge. I lost 36 pounds.”

In the two years since the trial ended, Patterson gained back 10 pounds.

There were unexpected benefits from taking Contrave, likely due to the makeup of the pill which is a combination of the antidepressant bupropion, which sells under several brand names including Wellbutrin, and the drug and alcohol addiction treatment naltrexone.

She didn’t experience increases in blood pressure or heart rate, side effects that triggered the FDA’s rejection of the drug and a request for another large clinical trial of the therapy.

Regulators have ordered additional tests of the other two drug candidates as well, though the parameters of those studies likely will be far less burdensome than the ones for Contrave.

Arena Pharmaceuticals of San Diego must examine the risk of heart-valve problems in patients taking lorcaserin and figure out why some rats developed tumors after receiving high doses of the drug.

Vivus of Mountain View has to study if its pill Qnexa increases the risk of birth defects. The company also must show that elevated heart rates in some patients aren’t tied to heart attacks or strokes.

Because of the long lead time it takes to get a drug candidate from the research laboratory to the market, new therapies often are based on outdated science.

That’s essentially the case with Contrave, lorcaserin and Qnexa, which have all been on the drawing board for at least eight years.

Part of the problem is the fact that eating behaviors are driven by a complex web of psychological mechanisms rather than a single factor that can be neatly altered with a single drug, said Dr. Jerrold Olefsky, an endocrynologist and associate dean for science at the University of California San Diego.

“If you were a hunter-gatherer way back when and you had an opportunity to eat a giant meal, you would gobble down everything possible because you may not eat for another week,” he said. “That’s the way we’re wired.”

Such biological complexity likely explains why weight loss with the current crop of experimental diet pills is fairly minimal.

It’s also why the next generation of diet drugs likely will attack the problem outside of the brain.

The search for new drug pathways that alter the body’s metabolism, and the way calories are burned and stored as fat, gained momentum in 2009 when researchers from the University of Michigan, Vanderbilt University and Fudan University in Shanghai published a paper in the journal Cell exploring the relationship between inflammation in the fat tissue of mice and obesity and diabetes.

They focused on a protein that activates immune-system white blood cells that cause fat cells to swell.

In regular mice that were fed a high-calorie diet, the protein activated white blood cells, causing fat cells to swell. The mice gained weight and became insulin-resistant, a condition known as Type 2 diabetes.

Another group of mice were genetically engineered to lack the protein. Those animals were also overfed, but they didn’t gain weight. Instead, their bodies consumed more oxygen and produced greater amounts of another type of protein that generates body heat by burning fat tissue.